This invention relates to a CCI-779 polymorph, processes for its preparation and pharmaceutical compositions and kits containing said polymorph.
Rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779) is an ester of rapamycin. Rapamycin, also termed sirolimus, is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus. The preparation and use of hydroxyesters of rapamycin, including CCI-779, are described in U.S. Pat. Nos. 5,362,718 and 6,277,983.
CCI-779 has been described as having in vitro and in vivo activity against a number of tumor cell types. It is hypothesized that CCI-779 delays the time to progression of tumors or time to tumor recurrence. This mechanism of action is more typical of cytostatic rather than cytotoxic agents and is similar to that of sirolimus.
CCI-779 binds to and forms a complex with the cytoplasmic protein FKBP, which inhibits an enzyme, mTOR (mammalian target of rapamycin, also known as FKBP12-rapamycin associated protein (FRAP)). Inhibition of mTOR's kinase activity inhibits a variety of signal transduction pathways, including cytokine-stimulated cell proliferation, translation of mRNAs for several key proteins that regulate the G1 phase of the cell cycle, and IL-2-induced transcription, leading to inhibition of progression of the cell cycle from G1 to S.
The preparation and use of hydroxyesters of rapamycin, including CCI-779, are described in U.S. Pat. Nos. 5,362,718 and 6,277,983.